Background
Myelodysplastic syndrome (MDS) is characterized by a heterogeneous hematological malignancy with a wide spectrum of presentation and implications. MDS with myelofibrosis (MF) accounts for 10%–20% of patients with de novo MDS [
1,
2]. A series of prognostic scoring systems was established to guide treatment strategies for patients with MDS, such as the Revised International Prognostic Scoring System (IPSS-R) [
3] and Molecular International Prognostic Scoring System (IPSS-M) [
4]. Notwithstanding that MF is not widely included in scoring systems and is not always considered when making treatment decisions, it has been confirmed to be an independent risk factor for prognosis of MDS cases without transplantations [
2,
5]. As reported previously, moderate to severe MF in primary MDS is significantly associated with multilineage dysplasia, transfusion dependence, and severe cytopenia [
6‐
8]. A large study including 2,624 patients with MDS revealed that grade 3 MF contributed to a decreased survival rate, irrespective of IPSS-R [
9]. Compared with patients without MF, a poor response to azacitidine was observed in patients with MDS concurrent MF [
10]. Recently, the fifth edition of the World Health Organization (WHO) classification identified MDS with fibrosis (MDS-f) as a subentity [
11].
Historically, emerging studies have been conducted to investigate the impact of MF on clinical outcomes of MDS cases under circumstance of allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the studies were quite inconclusive. It was recommended that the influence of MF should be factored in when allo-HSCT was proposed [
12]. Previous studies confirmed that MF was closely associated with delayed engraftment and an inferior event-free survival following allo-HSCT [
13,
14]. However, a recent study revealed that allo-HSCT may overcome the detrimental impact of moderate-to-severe MF on prognosis in patients with MDS. A significantly superior survival was observed in the allo-HSCT cohort compared to those without allo-HSCT (2-year overall survival [OS] rate, 68.4% versus 19.2%) [
15]. At the meanwhile, a few of studies indicated that the MF degree had no impact on prognosis of MDS in patients receiving allo-HSCT [
16,
17]. Taken together, the influence of MF on prognosis of MDS following allo-HSCT remains controversial. Therefore, we conducted a retrospective study to investigate the clinical characteristics, outcomes, and impact of MF on prognosis in patients with MDS following allo-HSCT.
Discussion
In this retrospective study, we enrolled 153 patients diagnosed with primary MDS who underwent allo-HSCT to explore the effect of MF on the prognosis of transplantation. We found that patients with MF-2/3 had comparable survival with those with MF-0/1 under the circumstances of allo-HSCT (2-year OS, 71.8% vs. 76.6%, P = 0.479; 2-year PFS, 68.4% vs. 72.8%, P = 0.380). Major/bidirectional incompatible ABO blood type between donors and recipients resulted in inferior survival of patients with MDS than those with compatible or minor incompatible ABO blood type. Patients with MDS-IB may benefit from strategies for achieving CR at the time of transplantation or MAC regimen.
Historically, moderate to severe MF was considered an adverse factor for prognosis in patients diagnosed with MDS without allo-HSCT, which could be attributed to multilineage dysplasia, excess of blasts, and increased risk of early BM failure or leukemia transformation [
2,
6,
26]. Similarly, some studies indicated that MF-2/3 was an adverse risk factor for outcomes in patients diagnosed with MDS who underwent allo-HSCT. As previously revealed, MF was an independent risk factor for OS rather than leukemia-free survival in the cohort after allo-HSCT [
1].Wang et al
. compared the survival in the MF-2/3 cohort and those in the MF-1 and MF-0 cohorts, and found an inferior estimated 3-year OS and PFS rate in patients with MF-2/3 following allo-HSCT (OS, 41.3% vs. 72.2% vs. 67.5%,
P = 0.018; PFS, 44.8% vs. 72.8% vs. 68.8%,
P = 0.018) [
14]. They also indicated that MF predicted an inferior survival in individuals with ≥ 10% blasts in BM at diagnosis. In the subgroup with BM blasts of < 10%, cases of MF-2/3 had a comparable survival rate with those with MF-1 and MF-0 [
14]. However, Scott et al
. reported no significant differences in OS, relapse-free survival, and NRM between patients with MF and those without [
16]. Remarkably, they found that MF was correlated with adverse transplantation prognosis in patients with advanced disease (int-2 or high-risk by IPSS) [
16]. In our study, no association between MF grade and transplantation outcomes was observed, regardless of whether in the entire cohort or in the MDS-IB subgroup. The controversial results may be attributed to the available patients in our study, in which we excluded those transformed to AML before transplantation. Previous reports have revealed that MF is associated with a higher rate of leukemia transformation [
14,
26], which may result in poor survival in patients with MDS. A previous study demonstrated that patients diagnosed with MDS concurrent with MF could achieve better survival in the allo-HSCT cohort than those without allo-HSCT [
15]. In addition, they indicated no significant difference in survival between the MF-2/3 and MF-0/1 cohorts in allo-HSCT recipients. On the other hand, our study confirmed that MF has no significant impact on engraftment and NRM after transplantation. Nevertheless, some studies have found that moderate to severe MF results in delayed engraftment and transfusion independence, leading to a high risk of NRM following allo-HSCT [
8,
14].
It remains controversial whether donor–recipient ABO blood type had a significant influence on transplantation outcomes. We demonstrated that major/bidirectional ABO incompatibility was a poor predictor of OS and PFS in patients diagnosed with MDS. In terms of the MDS-IB subgroup, a higher risk of relapse and NRM was observed in the major/bidirectional ABO-mismatched cohort. In line with our findings, Logan et al
. confirmed that major ABO incompatibility predicted a higher risk of NRM and poor OS in patients with MDS and AML [
27]. In the context of human leukocyte antigen-matched transplantation, a major ABO mismatch was independently associated with survival in patients with acute leukemia [
28]. Moreover, major ABO incompatibility was correlated with delayed multilineage engraftment, leading to a relative long-term transfusion dependence and increased NRM [
29]. Notwithstanding, Kimura et al
. found that ABO blood type mismatch has lost its detrimental effect on clinical outcomes in unrelated BM transplantation [
30]. In the myeloablative haploidentical transplantation, no association was noted between ABO blood type status and transplantation outcomes in patients diagnosed with hematological malignancies, where MDS accounted for 8% of the entire cohort [
31]. Taken together, we hypothesized that the impact of ABO incompatibility could vary depending on the disease and donor type. For patients diagnosed with MDS, particularly for MDS-IB, the ABO blood type should be carefully considered when several candidate donors are available.
In our study, patients with MDS-IB benefited less when they were NCR at the time of transplantation or received the RIC regimen. NCR at allo-HSCT significantly increased the risk of NRM, leading to inferior OS and PFS. In alignment with our study, it was revealed that patients with MDS who achieved CR before allo-HSCT had improved outcomes [
14]. Recently, it was confirmed that pre-HSCT MRD positivity was an independent risk factor for transplant outcomes in patients with MRD with excess blasts, along with the 3-year OS rates of 91.3% and 66.4% in the MRD-negative and MRD-positive cohorts, respectively [
32]. Remarkably, reducing tumor burden was recommended in patients with ≥ 10% BM blasts, especially when RIC was planned [
33]. The present study compared recipients with the RIC regimen, and a significantly lower incidence of relapse and superior survival was observed in those with the MAC regimen. Similarly, a long-term follow-up study by EBMT revealed that the 13-year relapse rate in patients with MDS was significantly higher in the RIC regimen than in the MAC regimen (48% vs. 31%; HR, 1.5; 95% CI 1.1–1.9;
P = 0.04) [
34]. In addition, a prospective phase III randomized study reported that patients with AML/MDS in the MAC cohort had superior OS compared with those in the RIC cohort [
35]. However, a CIBMTR retrospective study revealed similar OS and PFS between the RIC and MAC regimens in patients with AML/MDS with a high to very high risk of refined DRI [
36]. The presence of heterogeneous patients across different studies has posed challenges in explaining the contradictory results. To some extent, graft failure decreased in patients receiving the MAC regimen [
37], which may facilitate superior survival in patients with MDS concurrent with MF.
Despite these important findings, our study is subject to several limitations. This study was conducted retrospectively so that enrolled patients and clinical data have an inherent bias. In addition, this study is featured by a relatively small size from a single center, which may have an influence on the results. Therefore, large prospective research conducted by multiple centers is required to assess the impact of clinical characteristics on transplantation outcomes in individuals diagnosed with MDS, particularly in cases concurrent with MF.
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